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Methods for Chemical Equivalence in characterizing of complex molecules

a technology of complex molecules and chemical equivalence, which is applied in the field of analytical/statistical methods for characterizing, comparing, grouping and identifying complex molecules, can solve the problems of complex molecules such as monoclonal antibodies, peptides, polypeptide mixtures, etc., and achieves the effects of reducing the number of complex molecules, and improving the quality of complex molecules

Active Publication Date: 2014-02-04
SCINOPHARM TAIWAN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]The signals / spectra from a variety of analytic instruments coupled with multiple variant analysis can potentially provide meaningful comparative information of the complex molecules.

Problems solved by technology

Complex molecules, such as peptides, peptide mixtures, polypeptide mixtures, proteins, protein mixtures, biologics and biosimilars (or called follow-on-biologics) especially monoclonal antibodies, are extremely difficult to characterize, group and identify in contrast to small chemical molecules.
Due to the high complexity of some biologics, the products produced by different manufacturing processes can only be similar.
It is nearly impossible to obtain the products that are exactly the same.
Biologics, especially larger biologics, tend to be produced as diverse mixtures of molecules that differ very slightly from one another, which make them difficult to characterize.

Method used

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  • Methods for Chemical Equivalence in characterizing of complex molecules
  • Methods for Chemical Equivalence in characterizing of complex molecules
  • Methods for Chemical Equivalence in characterizing of complex molecules

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Protected Copolymer-1

[0042]N-carboxyanhydride of L-alanine (4.0 g, 34.78 mmol), N-carboxyanhydride of γ-benzyl L-glutamate (3.0 g, 11.39 mmol), N-carboxyanhydride of N-trifluoroacetyllysine (7.47 g, 27.97 mmol), and N-carboxyanhydride of L-tyrosine (1.6 g, 7.73 mmol) were placed in a single-neck flask with a magnetic stirrer. This mixture was dissolved by adding dry dioxane (289 mL). Distilled diethylamine (60 μL) was added. The resulting mixture was stirred mechanically for 24 hours at room temperature. Acetone (116 mL) was added to the mixture and the solution was slowly poured into a mixture of acetone (173 mL) and water (578 mL). The suspension was stirred and filtered. The solid was dried under vacuum at NMT 45° C. to give 12.02 g protected copolymer-1 (94.7% of yield).

example 2

Deprotection of Benzyl Group From poly[L-Ala, 5-benzyl-L-Glu, N6-TFA-L-Lys, L-Tyr] to poly[L-Ala, L-Glu, N6-TFA-L-Lys, L-Tyr]

[0043]12.02 g of protected copolymer-1, from Example 1, was suspended in 72 mL of 33% HBr / HOAc. The mixture was stirred at room temperature for 17 hours and the solution became clear. The mixture was extracted and washed with n-heptane (190 mL). The lower layer of the mixture was transferred into a mixture of water (240 mL) and n-heptane (120 mL). The precipitate was filtrated and dried to give trifluoroacetyl-glatiramer as a white solid.

example 3

Deprotection of Trifluoroacetyl Group From poly[L-Ala, L-Glu, N6-TFA-L-Lys, L-Tyr] to poly[L-Ala, L-Glu, L-Lys, L-Tyr]

[0044]9.5 g of trifluoroacetyl-glatiramer, from Example 2 was reacted with water (120.2 mL) and 40% tetrabutylammonium hydroxide in water (52.2 mL, 3 eq) for 24 hours at room temperature. The pH of the mixture was adjusted to 3˜4 by acetic acid (20 mL) to give a glatiramer acetate solution, and ultrafiltration was conducted by using a 3 kilodalton membrane to remove the low-molecular weight impurities. After 2 cycles of continuous water ultrafiltration, the resulting product is concentrated and lyophilized to give glatiramer acetate (Copolymer-1) as a pure white solid (4.7 g, 60% yield).

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Abstract

The present invention provides for a method of characterizing and classifying a sample containing a complex molecule, such as a peptide or polypeptide mixture, protein, protein mixture, biologic and biosimilar by using physical analysis, such as mass spectrometry, and statistic methods.

Description

RELATED APPLICATIONS[0001]This application is a continuation-in-part application of U.S. patent application Ser. No. 12 / 775,747, filed May 7, 2010, which claims priority from U.S. Provisional Patent Application Ser. No. 61 / 298,367 which was filed on Jan. 26, 2010.FIELD OF INVENTION[0002]The present invention relates to an analytic / statistical method for characterizing, comparing, grouping and identifying complex molecules such as peptides and polypeptide mixtures, proteins and protein mixtures, and biologics, biosimilars (or called follow-on-biologics) especially monoclonal antibodies. More particularly, the present invention provides a method of characterizing samples containing such complex molecules and, more particularly, comparing reference standards and the samples based on the information obtained by characterizing the reference standards and the samples with a variety of analytic instruments. The samples may be optionally pretreated by chemical or biological digestion. The i...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): H01J17/26
CPCG01N33/6848
Inventor CHAN, HARDYSHIEA, JENTAIE
Owner SCINOPHARM TAIWAN LTD
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